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Acute myeloid leukemia (AML) intensive chemotherapy combined with broad-spectrum antibiotics, leads to gut microbiota dysbiosis promoting pathological conditions and an increased incidence of complications. Here we report findings from a phase II single-arm, multicenter study evaluating autologous fecal microbiota transfer (AFMT) in 25 AML patients treated with intensive chemotherapy and antibiotics (ClinicalTrials.gov number: NCT02928523). The co-primary outcomes of the study are to evaluate the efficacy of AFMT in dysbiosis correction and multidrug-resistant bacteria eradication. The main secondary outcomes are to define a dysbiosis biosignature, to evaluate the effect of dysbiosis correction on patient clinical status, to assess the short and mid-term safety of AFMT in this immunocompromised population, and to evaluate the feasibility of the AFMT procedure and acceptability by the patient. Intensive induction chemotherapy induces a dramatic decrease of α-diversity indices, and a microbial dysbiosis with a significant shift of the microbial communities and domination of pro-inflammatory families. After AFMT treatment, α-diversity indices return to their initial mean levels and the similarity index shows the restoration of microbial communities. The trial meets pre-specified endpoints. AFMT appears to be safe and may be effective for gut microbiota restoration in AML patients receiving intensive chemotherapy and antibiotics, with an excellent gut microbiota reconstruction based on both richness and diversity indices at the species level., The combination of chemotherapy and broad-spectrum antibiotics induces gut microbiota (GM) dysbiosis in acute myeloid leukaemia (AML) leading to additional complications. Here, the authors report the efficacy in GM restoration and safety of autologous faecal microbiota transfer in treated AML patients in a phase II clinical trial.

Inherited thrombocytopenias correspond to a group of hereditary disorders characterized by a reduced platelet count, platelet dysfunction, and a family history of thrombocytopenia. It is commonly associated with mucocutaneous bleeding. Thrombocytopenia results from mutations in genes involved in megakaryocyte differentiation, platelet formation, and clearance. Here we report on a patient presenting with severe syndromic inherited thrombocytopenia manifesting as spontaneous mucocutaneous bleeds, requiring frequent platelet transfusions. Thrombocytopenia was explained by the presence of 4 mutations in 3 hematopoietic transcription factor genes: FLI1, RUNX1, and ETV6. The patient was successfully treated with high-dose eltrombopag at 150 mg/day, an orally available non-peptide thrombopoietin receptor agonist. Since the start of treatment 23 months ago, the manifestations of bleeding have resolved, and no platelet transfusions or corticosteroids have been required. The patient has no clinical or laboratory evidence of myeloid malignancy so far.

Immune reconstitution after allogeneic-hematopoietic-stem-cell transplantation (allo-HSCT) is a complex and individual process. In this cross-sectional study, whole-blood (WB) immune functional assay (IFA) was used to characterize immune function by assessing immune-related gene/pathway alterations. The usefulness of this tool in the context of infection, 6 months after transplantation, was evaluated. Sixty allo-HSCT recipients at 6 months after transplantation and 10 healthy volunteers (HV) were included. WB was stimulated in standardized TruCulture tubes using lipopolysaccharides and Staphylococcal enterotoxin B. Gene expression was quantified using a custom 144-gene panel using NanoString nCounter technology and analyzed using Ingenuity Pathway Analysis. The relationships between immune function and clinical characteristics, immune cell counts, and post-transplantation infections were assessed. Allo-HSCT recipients were able to activate similar networks of the innate and adaptive immune response compared to HV, with, nevertheless, a lower intensity. A reduced number and a lower expression of genes associated with immunoregulatory and inflammatory processes were observed in allo-HSCT recipients. The use of immunosuppressive treatments was associated with a protracted immune reconstitution revealed by transcriptomic immunoprofiling. No difference in immune cell counts was observed among patients receiving or not receiving immunosuppressive treatments using a large immunophenotyping panel. Moreover, the expression of a set of genes, including CCL3/CCL4, was significantly lower in patients with Herpesviridae reactivation (32%, 19/60), which once again was not identified using classical immune cell counts. Transcriptional IFA revealed the heterogeneity among allo-HSCT recipients with a reduced immune function, a result that could not be captured by circulating immune cell counts. This highlights the potential added value of this tool for the personalized care of immunocompromised patients.

Objectives To assess population pharmacokinetics (PK) and pharmacodynamics (PD) of both piperacillin and tazobactam in neutropenia patients and examine dosage requirements related to the MIC distribution for Gram-negative bacteria involved in bloodstream infections (BSIs). Methods We conducted a prospective study including adult haematological malignancy patients with febrile neutropenia receiving piperacillin/tazobactam as short (30 min) or prolonged (4 h) intravenous infusions. Concentration data were analysed using a population approach. Dosing simulations with the final model investigated factors influencing the PK/PD of piperacillin/tazobactam quantified by fT>MIC or PTA for piperacillin and tazobactam, respectively. In parallel, the local MIC distribution of β-lactams was documented for Gram-negative bacteria involved in BSIs. Results Over 10 months, 31 patients were enrolled, with 11 (35.5%) short and 20 (64.5%) prolonged infusion regimens. A one-compartment model adequately described the data for both drugs. Prolonged infusion, increased serum alkaline phosphatase (ALP) values and renal function impairment were associated with increased piperacillin fT>MIC. For patients with normal or augmented renal CL, dosing regimens q8h or q6h with 30 min of infusion were insufficient to achieve acceptable PTA for piperacillin/tazobactam at the median MIC value of 8 mg/L. Prolonged infusion of large doses was associated with the best PTA for both piperacillin and tazobactam. Conclusions In a population of haematological malignancy patients with neutropenia, renal function and ALP influenced the PK of piperacillin/tazobactam. Prolonged intravenous infusion would optimize the PK of piperacillin/tazobactam, especially in the case of augmented renal CL and/or low-range bacterial susceptibility.

Venous thromboembolism (VTE) is a major complication of multiple myeloma (MM), occurring in 10% of patients. The VTE risk is increased when lenalidomide is used in combination with high-dose dexame...

Minimal residual disease (MRD) is now a powerful surrogate marker to assess the response to chemotherapy in acute myeloid leukemia (AML). DNMT3A mutation has been associated with adverse outcomes. In this study, we aimed to investigate the impact of DNMT3A status on NPM1 MRD predictive value for survival in a retrospective cohort of AML patients aged over 60 years old treated intensively. A total of 138 patients treated for NPM1-mutated AML in two French institutions were analyzed retrospectively. DNMT3A status did not influence the probability of having a ≥ 4log MRD1 reduction after induction. Only 20.4% of FLT3-ITD patients reached ≥ 4log MRD1 reduction compared to 47.5% in FLT3wt cases. A 4log reduction of NPM1 MRD was associated with a better outcome, even in FLT3-ITD mutated patients, independent of the allelic ratio. DNMT3A negative patients who reached a 4log reduction had a superior outcome to those who did not (HR = 0.23, p &lt, 0.001). However, postinduction NPM1 MRD1 reduction was not predictive of OS and LFS in DNMT3Amut patients. These results confirm that post-induction NPM1 MRD1 is a reliable tool to assess disease outcome in elderly AML patients. However, the presence of DNMT3A also identifies a subgroup of patients at high risk of relapse.

International audience; We report the results of the French Temporary Authorization of Use (ATU) compassionate program of letermovir for primary prophylaxis conducted in 21 transplant centers. Patients were CMV seropositive allogeneic hematopoietic cell transplantation recipients and at high risk for CMV infection. Primary prophylaxis was defined as initiation of letermovir between day 0 and day +28 post-transplant. Between November 2017 and January 2019, 96 patients with a median age of 56 years received letermovir and follow-up data were available for 78 patients. The median time from transplant to letermovir initiation was 4 days, and the median duration of exposure to letermovir was 78 days, with 57 patients still on treatment at the cutoff date. Letermovir was temporarily discontinued in 4 patients (5.1%) and stopped in 39 patients (50.0%), in most cases due to planned end of treatment (n = 16, 20.5%). Fifteen patients (19.2%) each presented one positive CMV PCR, in median 13 days after letermovir initiation. Clinically significant CMV infection was reported in 5 patients (6.4%). No CMV disease was reported. At least one adverse drug reaction was reported for 12 patients (15.4%). In this early access program, letermovir was effective with comparable results of the phase 3 study with a low rate of clinically significant CMV infection, including in patients who were at high-risk for CMV infection.

Torque teno virus (TTV) has been proposed as a surrogate biomarker of T-cell function in allogeneic–haematopoietic–stem-cell transplantation (allo-HSCT). Conflicting data exists regarding the value of TTV to assess the degree of immunosuppression. The aim of the present study was to investigate the correlation between TTV viral load and immune function. Using samples from a prospective cohort composed of healthy-volunteers (HV) and allo-HSCT recipients at 6 months post-transplantation, we assessed the correlation between TTV viraemia and immune cell counts or T-cell proliferation capacity post-phytohaemagglutinin stimulation. TTV viraemia was detected in 68% of HV (n = 80) and 100% of allo-HSCT recipients (n = 41, p &lt, 0.001), it was significantly higher in allo-HSCT recipients (3.9 vs. 2.1 Log copies/mL, p &lt, 0.001). There was no correlation between T-cell function and CD3+T-cell count (rho: 0.002) suggesting that T-cell count can normalise without full functional recovery. Furthermore, no significant correlation was observed between TTV viraemia and absolute total/subset lymphocyte counts (rho: &lt, 0.13). The highest correlation was observed between TTV viral load and T-cell proliferation capacity (rho: −0.39). We therefore report an inverse correlation between T-cell function and TTV viraemia that is independent of T-cell count. Monitoring of TTV viraemia could be a fast suitable option to objectively assess the competence of immune function in at-risk populations.

International audience; Data on immunogenicity and safety of the recommended revaccination schedule against diphtheria, tetanus, poliomyelitis, pertussis, Haemophilus influenzae type b (Hib), and hepatitis B in adult allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients are limited. This prospective single-center cohort study (April 2014 to March 2018) included adult allo-HSCT recipients referred to a dedicated vaccinology consultation and vaccinated with the pediatric combined diphtheria, tetanus, acellular pertussis, hepatitis B virus, inactivated poliovirus, and Haemophilus influenzae type b (DTaP(±HB)-IPV-Hib) vaccine (3 doses 1 month apart, booster dose 1 year later). The proportion of responders to tetanus, diphtheria, Hib, and hepatitis B vaccine and geometric mean concentrations (GMCs) of antibodies were assessed before and up to 24 months after vaccination. A total of 106 patients were vaccinated at a median (interquartile range) time of 12.4 (10 to 18.4) months post-transplant. At 5.3 (4.8 to 6.6) and 23.1 (21.1 to 25.1) months after vaccine initiation, high and sustained rates of protective antibody titers were achieved for tetanus (97.8% [95% confidence interval (95% CI), 92.4% to 99.7%], n = 91/93 and 100% [95% CI, 92% to 100%], n = 44/44), diphtheria (94.6% [95% CI, 87.9% to 98.2%], n = 88/93 and 90.9% [95% CI, 78.3% to 97.5%], n = 40/44), Hib (96.6% [95% CI, 90.4% to 99.3%], n = 85/88 and 93% [95% CI, 80.9% to 98.5%], n = 40/43), and hepatitis B (83.5% [95% CI, 73.5% to 90.9%], n = 66/79 and 81.1% [95% CI, 64.8% to 92%], n = 30/37). Underlying disease, stem cell source, chronic graft-versus-host-disease, and extracorporeal photopheresis differentially influenced GMCs of tetanus, diphtheria, and hepatitis B antibodies after 3 doses but not in the long term (24 months). Six (5.7%) patients experienced mild side effects. The pediatric DTaP(±HB)-IPV-Hib vaccine was safe and effective in eliciting a sustained protective humoral response in adult allo-HSCT recipients. Hepatitis B revaccination might be optimized by using higher antigen doses.

Objectives To study the management of chronic disseminated candidiasis (CDC) in patients presenting with acute leukemia. Patients and methods Single-center retrospective study of acute leukemia patients (2006–2015) to investigate three aspects of CDC: its impact on the time interval between diagnosis and hematopoietic stem cell transplantation, when required (non-parametric Wilcoxon-Mann-Whitney test); its impact on overall survival (Cox proportional hazard regression model); antifungal therapeutic strategies implemented. Results A total of 639 patients presenting with acute leukemia were included; 144 were transplanted and 29 developed CDC. CDC did not significantly increase the time interval between diagnosis and transplantation, nor did it impact the overall survival of recipients. An improved overall survival was observed in non-transplanted acute leukemia patients presenting with CDC. Conclusion CDC should not postpone transplantation if antifungal treatment is optimized.

Introduction. AML standard intensive induction chemotherapy ("3+7" or equivalent) combined with wide spectrum antibiotics can dramatically alter the composition of the gut microbiota, leading to dysbiosis which is characterized by loss of microbial diversity. Such dysbiosis status can promote a pathological condition involving uncontrolled local immune responses, systemic inflammation and increased incidence of adverse events. The development of FMT-based drugs to restore microbial communities could offer novel therapeutic possibilities to reduce such adverse events and potentially improve outcomes in AML. We therefore conducted this single arm prospective phase I/II multicenter trial (NCT02928523) to evaluate the use of a FMT-based drug in association with AML induction treatment to restore the gut microbiota diversity. Patients and methods. A total of 62 consecutive patients aged between 24 and 69 years old with a diagnosis of de novo AML were screened in 7 French sites. At time of admission and AML diagnosis (Step 1=S1), patients' faeces were collected, rigorously screened, prepared following a standardized process, and stored at -80°C until later administration. The drug was administered as an enema after hematopoietic recovery (S2) and before consolidation chemotherapy (Conso). The primary endpoint was the recovery of at least 70% of microbiota diversity (based on the Simpson index) after drug administration and the reduction of multidrug resistant bacteria carriage. Blood and feces samples were collected at S1, S2, and around 10 days post-FMT before Conso (S3). Microbiome diversity restoration was assessed by metagenomics analysis through Illumina HiSeq shotgun sequencing. Antibiotic resistance gene carriage (ARGC, also known as resistome) was evaluated through mapping of readouts on the MEGARES database. Secondary objectives included safety and analysis of host response with assessment of blood and fecal markers by ELISA and Luminex. Results. Overall, 25 patients were actually treated with FMT, and 20 were included in the per-protocol population. Induction Chemotherapy (IC) induced a dramatic shift in microbial communities, with a significant 42.3% decrease of mean α-diversity Simpson index between S1 and S2 at species level (0.85 to 0.50; p No serious adverse events (SAE) were observed within 30 days after FMT and all post FMT SAEs were not related to the FMT procedure. Moreover, FMT did not induce any local or systemic inflammatory reaction as measured by fecal and blood markers (fecal neopterin and IgA; plasmatic CRP, IL-6 and sCD14). Interestingly, restoration of the microbiome diversity was associated with a significant reduction of CRP and fecal neopterin levels, suggesting a potential anti-inflammatory impact of FMT. Overall, FMT was well tolerated and had an excellent safety profile. The one-year overall survival estimate in the whole cohort was 84% (4 deaths among 25, none of which were related to FMT: 2 multiple organ failures, 1 heart attack and 1 grade IV resistant GVHD). The median time to death from the second FMT was 182.5 days (113-225 days). Conclusions. This is the first prospective trial testing the safety and efficacy of FMT in AML patients receiving intensive induction chemotherapy. The trial achieved its primary endpoint and established the capacity of FMT to restore a diverse microbiome with high levels of similarity to baseline, as well as reducing ARGC and intestinal inflammation. A controlled randomized trial with repeated FMT administrations is currently planned to further evaluate the impact of FMT on clinical outcomes and long-term survival. (This trial was funded by MaaT Pharma whose product was tested in this protocol). Disclosures Mohty: MaaT Pharma: Consultancy, Honoraria. Doré:MaaT Pharma: Consultancy, Honoraria.

This study aims to evaluate the impact of implementing a specialized clinical pharmacy program in patients with allogeneic hematopoietic stem cell transplant (HSCT) on their adherence to the immunosuppression treatment after discharge. A prospective open interventional design using a retrospective control group was used. The intervention was based on pharmaceutical consultations: the first was performed the day before discharge of HSCT unit and the next consultations during day-care follow-up (weeks 2 and 4 after discharge). Proactive medication reconciliation was implemented with a complete list of medications before the discharge prescription. The discharge prescription summarized on a personalized drug schedule was explained to the patient. The importance of optimal adherence and the potential problems related to self-medication were explained to the patient. Immunosuppression drug adherence was assessed by a direct method using serum levels of calcineurin inhibitors. The potential impact on acute GvHD, and infection was investigated. Twenty-six patients were included in the specialized clinical pharmacy program and 35 patients were in the control group. Seventy-nine pharmaceutical consultations were conducted in the intervention group, lasting a mean 25 min and 16 min for the first and following consultations, respectively. Serum levels in the therapeutic target range were higher in the intervention group (61.5% versus 53.0%, p = 0.07), with greater intra-individual variation (p = 0.005). There was no significant intergroup difference in acute GvHD (53.8% versus 50.3%, p = 0.85) or infection (26.9 versus 22.8%, p = 0.72). The implementation of a specialized clinical pharmacy program for patients who have received allogeneic HSCT seems to be beneficial for immunosuppression drug adherence; this now needs to be confirmed in a multicenter study involving a larger number of patients.

Although numerous factors have been found to modulate hTERT transcription, the mechanism of its repression in certain leukemias remains unknown. We show here that DEK represses hTERT transcription through its enrichment on the hTERT promoter in cells from chronic and acute myeloid leukemias, chronic lymphocytic leukemia, but not acute lymphocytic leukemias where hTERT is overexpressed. We isolated DEK from the hTERT promoter incubated with nuclear extracts derived from fresh acute myelogenous leukemia (AML) cells and from cells expressing Tax, an hTERT repressor encoded by the human T cell leukemia virus type 1. In addition to the recruitment of DEK, the displacement of two potent known hTERT transactivators from the hTERT promoter characterized both AML cells and Tax-expressing cells. Reporter and chromatin immunoprecipitation assays permitted to map the region that supports the repressive effect of DEK on hTERT transcription, which was proportionate to the level of DEK-promoter association but not with the level of DEK expression. Besides hTERT repression, this context of chromatin redistribution of DEK was found to govern about 40% of overall transcriptional modifications, including those of cancer-prone genes. In conclusion, DEK emerges as an hTERT repressor shared by various leukemia subtypes and seems involved in the deregulation of numerous genes associated with leukemogenesis.

Introduction Les receveurs d’allogreffe de cellules souches hematopoietiques (ACSH) ont un risque accru d’infection invasive a pneumocoque (IIP). La vaccination anti-pneumococcique est recommandee des 3 mois post-ACSH, mais peu de donnees sont disponibles sur l’immunogenicite du schema vaccinal. Materiels et methodes Etude prospective monocentrique observationnelle de tous les receveurs d’ACSH adresses a une consultation de vaccinologie dediee entre 2014 et 2018 pour recevoir 3 injections mensuelles de vaccin polyosidique conjugue 13-valent suivies d’une 4e injection de vaccin polyosidique non conjugue 23-valent 6 mois plus tard. Les concentrations seriques d’immunoglobulines G (IgG) specifiques de 23 serotypes du pneumocoque (anti-PCP) ont ete mesurees par ELISA (VaccZyme™, The Binding Site Ltd) avant (T1) puis a 6 (T2), 12 (T3) et 24 mois (T4) apres le debut de la vaccination. Les moyennes geometriques des concentrations (GMC) d’anti-PCP ont ete comparees. Specifiquement a T2, une analyse univariee a ete utilisee pour etudier les facteurs influencant la concentration d’anti-PCP. Resultats Parmi les 125 receveurs d’ACSH adresses a la consultation, la concentration d’anti-PCP a T1 et T2 a ete mesuree chez 95 patients (H/F 1,6 ; âge median 48 ans, intervalle interquartile [IQR] 38–60). Le delai median entre ACSH et vaccination etait de 11,1 mois (IQR 8,6–16,5). Les GMC d’anti-PCP ont augmente de 35,6 mg/L (intervalle de confiance a 95 % [IC95] 28,9–43,8) a T1 a 98,8 mg/L (IC95 80,6–121,3) a T2 (p Conclusion La vaccination anti-pneumococcique est globalement immunogene apres ACSH. Nos resultats suggerent que son efficacite depend de l’hemopathie sous-jacente et est diminuee en cas de photochimiotherapie extracorporelle.

International audience; Outcome of patients with primary refractory/relapsed (R/R) acute myeloid leukemia (AML) remains dismal. Herein, we present a retrospective monocentric study of 24 very high-risk AML patients who received a combination of fractionated gemtuzumab ozogamicin (GO) with intermediate-dose cytarabine and daunorubicin as salvage therapy. Median age was 55.3 years. Diagnostic was secondary AML for 33% of them. Seven patients had favorable risk, 8 had intermediate-1 or intermediate-2, and 6 had unfavorable risk of AML according to the European LeukemiaNet prognostic index. Complete remission was achieved in 50% of cases (46% in refractory and 55% in relapsed AML) without excessive toxicity. Thirteen patients could be referred for transplant. Only allogeneic hematopoietic stem cell transplantation provided a benefit in this patient cohort with a 1-year overall survival of 50.7 versus 18.1% in the absence of transplantation. Patients treated with reduced intensity conditioning (RIC) showed a longer survival as compared to those undergoing myeloablative conditioning regimen mainly because of decreased toxicity.Our data suggest that salvage therapy with fractionated GO combined with intermediate-dose cytarabine and daunorubicin in very high-risk patients may serve as a potential bridge therapy to RIC transplant

After allogeneic hematopoietic stem cell transplantation (HSCT), BK virus-associated hemorrhagic cystitis (BKV-HC) is a common complication. Although supportive measures have been the standard of care for many years, several studies suggested the efficacy of cidofovir. The aim of this study was to assess the safety profile and efficacy of cidofovir. A retrospective study was conducted on all patients treated with cidofovir in our HSCT unit between March 2011 and May 2013. Data for efficacy (partial [PR] or complete response [CR]), prescription (dose, frequency, number of doses, and administration route), and toxicity were collected from published reports and medical files. Renal toxicity was evaluated using creatinine clearance calculated with the Cockcroft and Gault formula. A parallel literature search using PubMed (last search, May 2015) was performed. From March 2011 to June 2013, 27 of 181 patients undergoing allogeneic HSCT in our department received cidofovir for BKV-HC: 24 (88.9%) intravenously, 1 intravesically, and 2 via both routes. Mean dose was 5 mg/kg per administration, for a median of 4 injections (range, 1 to 11), from twice a week to once every 2 weeks. CR was achieved in 22 patients (81.5%), PR in 2, and no response in 2 patients. Eight patients presented renal failure (29.6%): 6 moderate (creatinine clearance 60 mL/min) and 2 severe (creatinine clearance 30 mLmin). Mean decrease in creatinine clearance after cidofovir was 27% (35 mL/min; range, 2 to 159). In 3 cases renal insufficiency and hematologic toxicity led to discontinuation of treatment or switch to intravesical instillation. For 3 patients cidofovir dose was reduced because of nephrotoxicity. Thirteen studies have reported on the use of cidofovir for BKV-HC (204 patients) since 2005. Intravenous cidofovir was used for 91.3% of patients, with doses ranging from .5 to 5 mg/kg. The main toxicity reported was renal failure (9% to 50% in 9 studies). Between 60% and 100% of CRs were observed independently of cidofovir dose or administration route. Cidofovir is an effective therapy for BKV-HC but requires very precise renal function management to avoid toxicity. Cidofovir treatment modalities (high dose, intravesical instillation, or low dose [≤1 mg/kg]) needs to be investigated in randomized controlled trials.

International audience; OBJECTIVES: Human herpes virus 6 (HHV-6) can reactivate after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and may be associated with significant clinical manifestations. METHODS: Case control study of HHV-6 infections after allo-HSCT. Chromosomal integration (ciHHV-6) for viral loads \\textgreater/= 5.5-log10 copies/mL was investigated. Viral co-infections, T-cell recovery, risk factors and outcome were compared in HHV-6- and non-HHV-6-infected patients. Antiviral treatment strategies were reviewed. RESULTS: Among 366 adult allo-HSCT recipients, 75 HHV-6 infections occurred. Three (4%) recipients were ciHHV-6. HHV-6 infections were associated with CMV (p = 0.05; sdHR 1.73, CI 0.99-3.02) and/or BKV infections (p \\textless 0.0001; sdHR 4.63, CI 2.04-10.53) but not EBV reactivation (p = 0.34). A slower CD8+ T-cells recovery was observed until 6 months after allo-HSCT in the HHV-6-infected group (p \\textless 0.001), independently of acute and/or chronic graft-versus-host disease. The overall probability of survival after allo-HSCT was diminished for active HHV-6-infected patients (p = 0.0326). Cord blood unit recipients had a higher risk of developing HHV-6 infection compared to bone marrow recipients (p = 0.0007; sdHR 3.82, CI 1.76-8.27). Anti-HHV-6 treatment achieved complete response in only 2/3 of the cases. CONCLUSIONS: In this series of allo-HSCT recipients, 4% were ciHHV-6, active HHV-6 infection was likely associated with CMV and BKV co-reactivations, delayed CD8+ T-cell recovery and poorer outcome

International audience; Hormographiella aspergillata is a rare causative agent of invasive filamentous breakthrough infection, mostly arising after echinocandin exposure. We report a neutropenic patient who developed a severe sino-orbito-cerebral H. aspergillata infection while receiving empirical caspofungin, successfully controlled by an aggressive strategy associating surgical debridement and combined high-dose regimen of antifungal drugs.

The widespread use of acyclovir (ACV) and the increasing number of immunocompromised patients have raised concern about an increase in ACV-resistant herpes simplex virus (HSV). ACV resistance has traditionally been a major concern for immunocompromised patients with a frequency reported between 2.5% and 10%. The aim of this study was to reassess the status of HSV resistance to ACV in immunocompetent and immunocompromised patients over a ten year period, between 2002 and 2011. This was done by retrospectively following 1425 patients. In immunocompetent patients, prevalence of resistance did not exceed 0.5% during the study period; whereas in immunocompromised patients, a significant increase was observed, rising from 3.8% between 2002 and 2006 (7/182 patients) to 15.7% between 2007 and 2011 (28/178) (p = 0.0001). This sharp rise in resistance may largely be represented by allogeneic hematopoietic stem cell transplant patients, in which the prevalence of ACV resistance rose similarly from 14.3% (4/28) between 2002 and 2006 to 46.5% (26/56) between 2007 and 2011 (p = 0.005). No increase in ACV resistance was detected in association with other types of immune deficiencies. Genotypic characterization of HSV UL23 thymidine kinase and UL30 DNA polymerase genes revealed 11 and 7 previously unreported substitutions, respectively. These substitutions may be related to potential polymorphisms, drug resistance, or other mutations of unclear significance.

Treatment of a severe extensive cutaneous chronic GVHD after allo-HSCT using glycerolyzed skin allografts and cultured epidermis from the same donor

Introduction Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only curative strategy for a majority of patients with high-risk hematological malignancies. Several studies have evaluated the impact of conditioning intensity on the long-term transplantation outcomes, mainly retrospective and derived from large registries or non-randomized trials. These studies showed that more intensive conditioning (MAC) regimens are associated with a reduced risk of relapse, but do not translate into improvement of survival due to increased non-relapse mortality (NRM). Reduced intensity/Non-myeloablative conditioning (RIC/NMA) through graft-versus-leukemia effect has been associated with lower NRM, but higher relapse rates leading to similar overall survival (OS) when compared to MAC. However, in daily clinical practice, these results are difficult to follow because of the combination of important impact of disease stage, the type of HSC donor and its HLA matching with the patient. In addition, the historical nature of the previous studies may lead to the observation of different results today as the experience in drugs toxicities management has changed over time. The objective of this study is to evaluate the impact of the conditioning regimen intensity taking into account the disease stage and the type of HSC donor with its HLA matching on transplantation outcomes in a large population of patients with high-risk hematological malignancies. Material and methods A total of 542 patients who received allo-HSCT between January 2006 and December 2014 in our center were included, 321 (59%) were males, the median age at allo-HSCT was 49 years (range: 18-70). There was 256 (47%) acute leukemia (202 AML, 54 ALL), 61 (11%) MDS, 60 (11%) multiple myeloma, 46 (8%) NHL, 25 (5%) Hodgkin's disease, 23 (4%) myeloproliferative neoplasms, 21 (4%) CML, 12 (2%) CLL and the rest with other hematological diseases. All patients were classified as at high-risk according to either clinical, immunophenotypic, cytogenetic or molecular markers. Conditioning regimen was classified as recently published (Gyurkocza et al. Blood 2014), therefore 282 (52%) received MAC and 260 (48%) received RIC/NMA; at allo-HSCT 320 (59%) patients were in CR and 222 (41%) in less than CR. HSC donor was identical siblings (Sib) for 199 (37%) patients (100 BM, 99 PBSC), 10/10 HLA matched unrelated (MUD) for 159 (29%) (79 BM, 80 PBSC), 6/6 HLA matched double cord blood (CB) units for 12 (2%), 9/10 HLA mismatched unrelated (MMUD) for 114 (21%) (54 BM, 60 PBSC), and the rest of 58 (11%) were 5/6 or 4/6 MM double CB units. For sex mismatching, in 119 (22%), it was female donor to a male patient; 295 (54%) were ABO compatible, 105 (20%) had minor incompatibility and 142 (26%) major incompatibility. Results The median follow-up for surviving patients was 29 months (range: 4-96). We conducted a cox multivariate model for OS including patient age, disease status at allo-HSCT, conditioning regimen, type of donor and HLA matching, in addition to ABO and sex mismatching, with stratification on the type of disease; this model showed a significant impact of disease status in favor of CR (HR=1.5, 95%CI: 1.2-2.0, p=0.001), conditioning regimen in favor of MAC (HR=0.68, 95% CI: 0.53-0.88, p=0.003) and type of donor in favor of Sib (HR=0.68, 95%CI: 0.5-0.9, p=0.01). Interestingly, we were able to find an optimal association between these 3 factors leading to significantly better results in terms of OS and NRM independently of the disease type. When in CR, patients receiving MAC from Sib or from MUD had significant better OS and NRM compared to the rest of patients with 5-years rates of 71% vs 36% (p Conclusion We provide in this large study, a practical daily clinical practice outcome preview after allo-HSCT, independently of the type of disease, for the combination of significant impacting factors namely disease status at allo-HSCT, conditioning regimen and type of HSC donor with a superiority for MAC when used in CR from Sib or MUD. Figure 1. Figure 1. Disclosures Nicolini: Ariad Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Introduction: Anemia is the most common hematological abnormality in patients with cancer and hematological malignancies, and is associated with poor prognosis and outcomes that have a detrimental impact on the patient's condition and quality of life (QOL). Erythropoiesis-stimulating agents (ESA) represent a good treatment option in order to increase the hemoglobin level in patients with anemia. Anemia can also be treated by red blood cell transfusion, but this has a transient effect and is associated with risks such as exposure to infectious agents, iron overload, or transfusion-related acute lung injury. ESA also have safety concerns, including the established increased risk of venous thromboembolic events. However, they are currently the only therapeutic alternative to transfusions. We performed a prospective observational study in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) for hematological malignancies, with the primary objective of evaluating the effect of a new ESA biosimilar, epoetin zeta (Hospira) on patient QOL. Secondary objectives included hemoglobin (Hb) and platelet (Pt) recovery, safety, overall survival (OS) and relapse incidence. Results of this study were compared to two reference populations, one receiving epoetin beta (Roche) and one control group not treated with ESA. Here, we present preliminary results for the secondary objectives. Materials and methods: The study included adult patients with Hb level ≤11g/dl occurring after all types of allo-HSCT for any hematological disease (Table 1). Epoetin zeta (30,000 IU) was administered s.c. once per week for up to 6 months, and Hb levels were monitored weekly. Injections were stopped once the Hb level reached 12g/dl without transfusion. If after 4 injections, no improvement was observed, doses were doubled, and if after 8 injections, no improvement was observed, the patient was withdrawn from the study. The QOL was measured at baseline and at 1, 2, 3 and 6 months by the Functional Assessment of Cancer Therapy-Anemia (FACT-An) scale. Epoetin zeta responders were defined as having Hb level ≥12g/dl (complete response, CR) or a ≥2g/dl increase (partial response, PR) compared with baseline value, in the absence of transfusion. Patients receiving epoetin zeta (group 1) were compared to a similar population receiving epoetin beta with the same procedures (group 2) and to a matched population not treated with ESA (group 3), taking into account the following variables: sex, age, diagnosis, disease status at allo-HSCT, conditioning regimen and HSC source. Results: Between December 2011 and September 2014, 58 patients (from 168 screened) were included in group 1, and compared to 59 patients in group 2 and 65 patients in group 3. The main exclusion criteria were ESA contra-indication and patient refusal. Patients in group 1 had lower Hb baseline levels compared to group 2; patient characteristics for each group are summarized in Table 1. The median number of injections/patient was 10 (range: 6-14) in group 1 and 8 (range: 2-28) in group 2. The cumulative incidence of CR was 80% in group 1 and 71% in group 2. The median time to achieve CR was 48 days (range: 35-70) in group 1, and 39 days (range: 14-180) in group 2. Eight patients withdrew due to ESA inefficacy in group 1 and 8 in group 2. Adverse events were all thromboembolic: 2 events in group 1 and 5 events in group 2, compared to 2 events in group 3 (p=0.34). The multivariate analysis studying different confounding factors on the cumulative incidence of CR showed a significant positive impact of younger age (p=0.001), and a negative impact of being female or having major ABO incompatibility. We did not find any significant difference in terms of OS and relapse rate between the 3 groups. Conclusion: We describe here, for the first time, preliminary data for ESA biosimilar epoetin zeta (Hospira) in allo-HSCT patients showing comparable efficacy and safety to an existing ESA, epoetin beta (Roche) with no impact on OS and relapse incidence, compared to a control group. The QOL and transfusion evaluations as well as a cost-effectiveness study are ongoing and results will be presented. Disclosures Nicolini: Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Ariad Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Introduction Allogeneic hematopoietic stem cell transplantation (allo-HSCT) from unrelated donors has been increasingly used worldwide in the last decade in patients with hematological malignancies when HLA-identical sibling donors are unavailable. Identification of the HLA locus matching at the allele level is important in optimizing transplantation outcomes by minimizing non-relapse mortality (NRM) as well as in enhancing the graft-versus-leukemia effect. It has been demonstrated that patients with HSC donors matched on HLA-A, -B, -C, -DRB1, and -DQB1 alleles can have different outcomes if considering matching on HLA-DPB1 allele. HLA-DPB1 mismatches based on T-cell-epitope groups could identify mismatches that might be tolerated (permissive) and those that would negatively impact transplantation outcomes (non-permissive). We conducted this study to evaluate the impact of HLA matching degree between patient and HSC donor including HLA-DPB1, taking into account the other impacting variables in the allo-HSCT settings. Material and methods A total of 235 patients who received allo-HSCT at our center between January 2005 and December 2014 with a full donor/recipient HLA class I and II locus available data were included, 131 (56%) were males, the median age at allo-HSCT was 50 years (range: 18-69). There was 123 (53%) acute leukemia (93 AML, 30 ALL), 24 (10%) MDS, 35 (15%) multiple myeloma, 20 (8%) NHL, 7 (3%) Hodgkin's disease, 10 (4%) myeloproliferative neoplasms, 13 (6%) CML, and 3 (1%) CLL. One hundred and nineteen patients (51%) received myeloablative conditioning (MAC) and 116 (49%) received reduced intensity conditioning (RIC). Disease status at allo-HSCT was complete remission (CR) in 144 (61%) patients and less than CR in 91 (39%). HSC donor was 10/10 HLA matched unrelated (MUD) for 162 (69%) (80 PBSC and 93 BM), among them 21 (9%) were matched for HLA-DPB1, 41 (18%) had permissive mismatch and 100 (42%) had non-permissive mismatch; while 73 (31%) had 9/10 HLA mismatched donor MMUD (48 PBSC and 25 BM), among them, 7 (3%) were matched for HLA-DPB1, 12 (5%) had permissive mismatch and 54 (23%) had non-permissive mismatch; 110 (47%) were ABO compatible, 58 (24%) had minor incompatibility and 67 (29%) had major incompatibility. For sex mismatching, in 33 (14%) cases, it was female donor to a male patient. Results After a median follow-up for surviving patients of 29 months (range: 4-108), patients with 10/10 HLA MUD had better overall survival (OS) than those with 9/10 MMUD without considering the HLA-DPB1 matching, with 2 years OS probability of 51% vs 35% respectively (p=0.09), which was reflected by a lower NRM at 2 years of 29% vs 42% (p=0.07). When considering the HLA-DPB1 matching, we found comparable outcomes in terms of OS and NRM for: 1) 10/10 HLA MUD - DPB1 matched vs 10/10 HLA MUD - DPB1 permissive mismatched, 2) 10/10 HLA MUD - non-permissive DPB1 mismatched vs 9/10 HLA MMUD - DPB1 matched, 3) 9/10 HLA MMUD - DPB1 matched vs 9/10 HLA MMUD - DPB1 permissive mismatched; all these 3 groups were not significantly different between each other expect for a last group which included 9/10 HLA MMUD with non-permissive DPB1 mismatch, this group had worse OS and NRM compared to all others with 2 years rates of 34% vs 49% (p=0.05) and 47% vs 29% (p=0.04) respectively. In multivariate analysis, patient age (>50 years), disease status (less than CR), HLA matching (9/10 HLA MUD non-permissive DPB1) and sex mismatching (female donor to male patient) were significantly impacting OS and NRM. We included all these variables in a risk score: age < 50 years= 0, > 50 years= 1; CR= 0, less than CR= 1; HLA 10/10 (matched on DPB1) or HLA 10/10 with permissive MM on DPB1= 0; HLA 10/10 with non-permissive MM on DPB1 or HLA 9/10 (matched on DPB1 or with permissive MM on DPB1)=1; HLA 9/10 with non-permissive MM on DPB1=2; for sex matching, female donor to male patient=1, all other= 0. The risk score distinguished low risk patients (total score=0), intermediate (total score=1 or 2) and high risk (total score >2) with 2 years OS and NRM rates of 66%, 52%, 30% (p=0.003) and 22%, 29% 48% (p=0.004) respectively. Conclusion MMUD with non-permissive T-cell-epitope mismatch at HLA-DPB1 should be avoided due to increased rates of NRM. The risk score combining HLA matching with age, disease status and sex matching is very helpful for daily clinical practice offering patients better treatment strategy. Figure 1. Figure 1. Disclosures Nicolini: Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Ariad Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Introduction Invasive aspergillosis (IA) remains an important cause of mortality in immunocompromised acute myeloid leukemia (AML) patients receiving induction chemotherapy and in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) for hematological malignancies. Early diagnostic is critical and challenging given the efficacy and availability of several new anti-fungal therapies. In this study, we evaluated the performance of different factors in predicting the occurrence of IA, including the Aspergillus antigen galactomannan (GM) detection in sera. Methods We included all AML patients receiving induction chemotherapy and patients undergoing allo-HSCT for any hematological malignancy at our center between April 2006 and April 2014 with available data on Aspergillus antigen GM. Serologic detection of circulating GM fungal biomarker was considered during the 100 days following the first day of induction chemotherapy in AML patients or from the day of allo-HSCT. Usual follow-up included two GM tests per week, only patients with at least three serum GM results were considered. The GM tests have been performed routinely using the ELISA kit (Platelia Aspergillus antigen ELISA, Biorad), giving the results in index values. Demographic, GM index results and diagnostic data were collected. IA cases were classified as proven or probable according to the EORTC criteria. The value of the first antigen test, the delay to positivity, and the slope of the progression of the index value between the first two antigens concentrations were considered as predictors of IA. ROC curves for each predictor and their combination were performed and prognostic scores were established. Results A total of 775 patients were included : i) 292 AML patients, 153 (52%) males with a median age of 62 years (range: 17-79), 15% were classified as favorable, 8% as intermediate I, 18% as intermediate II and 59% as unfavorable according to cytogenetics and molecular markers; ii) 483 allo-HSCT patients, 293 (61%) were males, median age was 48 years (range: 18-70), among them 234 (48%) AML, 66 (14%) multiple myeloma, 46 (10%) Myelodysplastic syndromes, 38 (8%) Non-Hodgkin Lymphoma and the rest of patients had other hematological disorders; 233 (48 %) patients received reduced intensity conditioning and 250 (52%) myeloablative conditioning. The disease status at allo-HSCT was complete remission (CR) in 366 (76%) patients and the rest of patients were in less than CR. HSC source was peripheral blood in 42.2% (90 identical siblings, 150 10/10 matched unrelated, 54 9/10 mismatched unrelated), bone marrow in 42.6% (105 identical siblings, 162 10/10 matched unrelated, 45 9/10 mismatched unrelated) and cord blood in 15.2%. A total of 877 episodes with 16121 GM serum antigen results was considered (median: 18 GM tests per patient). During the follow-up, we identified 121 episodes with at least one positive GM test with a cumulative incidence at day 100 of 13.8%. We also diagnosed 48 IA (2 proven, 46 probable), with a cumulative incidence at day 100 of 5.5% in total, 7.2% in AML and 4.3% in allo-HSCT, respectively. We then classified the GM positive episodes in 82 false-positive (68%) and 39 true-positive episodes (32%) for IA, respectively. A majority of IA events occurred during the first 30 days of follow up, GM positivity showing a positive predictive value of 41% versus a negative predictive value of 99%. The three IA predicting factors had similar independent effects and their combinations were performed, allowing the establishment of an area under ROC of 0.79 (95% CI: 0.70-0.89). Cut off values of the first positive GM serum and slope were equal or higher than 1.04 and 0.04, respectively, and delay to positivity equal or less than 15 days. To simplify the practical use in clinical practice, the prognostic score defining the IA risk probability was defined as the number of predictors present (values from 0 to 3). This score was tested on positive follow-up giving values of 0, 1, 2 or higher for 45 (37%), 39 (32%) and 37 episodes (31%), respectively. A score superior or equal to 2 was indicative of IA in 62% of the cases (figure 1). Conclusion As IA has a significant impact on hematology patient's survival, this GM predictive score combining three predictors (value of the first antigen index, delay of positivity and slope of the index values) may help clinicians to conclude about starting an early preemptive IA treatment. Figure 1. Figure 1. Disclosures Nicolini: Ariad Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the main therapeutic option for most patients with high risk acute myeloid leukemia (AML). In order to determine whether time between diagnosis and allo-HSCT could have any impact on transplant outcomes, we screened 700 consecutive adult AML patients diagnosed between January 2007 and June 2014 at the Lyon Sud Hospital transplant center. Inclusion criteria were: (1) newly diagnosed AML in patients with age ≤ 65 years, (2) AML classified in the intermediate-2 and unfavorable risk groups according to the Acute Leukemia French Association (3) patients fit for receiving chemotherapy (4) patients candidates for allo-HSCT and in first complete remission (CR1) at transplantation. Two hundred and one patients met the inclusion criteria and were enrolled in the study. Among them, 137 (68%) received allo-HSCT of whom 83 (41%) only received HSCT in CR1 after a median time of 143 days (range: 69-265) from diagnosis. We collected within this interval different delays for donor search, including patients HLA typing and time to unrelated donor identification when a sibling donor was not available. Patients were split into 2 groups based on their time to transplant. An "early transplant group" included 28 (33%) patients transplanted after a median time of 108 days (range: 69-133) after diagnosis. The other 55 (67%) patients transplanted after a median time of 163 days (range: 134-265) were qualified as "late transplant group". Patients and transplantation characteristics according to the timing of transplantation are shown in table 1. After a median follow-up of 16 months (range: 0-60) the 5-year probability of overall survival (OS) and disease-free survival (DFS) for the whole population were respectively, 63.4% and 48.3%. The cumulative incidences of non-relapse mortality (NRM) at 1 and 5 years were constant at 17.5%. The multivariate analysis using proportional hazards modeling showed that conditioning regimen and sex mismatching were independent prognostic factors for DFS, with no significant impact on OS. To evaluate the long term impact of transplantation timing on OS and DFS, we performed a landmark analysis for patients surviving at 1 year post-allo-HSCT. This analysis showed that patients in the early transplant group had a higher probability of OS at 3 and 5 years with 100% survival respectively compared to the late transplantation group with 85.5% and 79.4% respectively (p=0.09); accordingly, we found a significant difference in terms of DFS with 100% probability at 3 and 5 years for the early transplantation group compared to 80% and 56% respectively in the late transplantation group (p=0.02). This difference in terms of OS and PFS was still valid after stratification on the type of conditioning regimen. These results confirm the important impact of allogeneic HSCT timing in high-risk AML patients, early allo-HSCT for patients transplanted in CR1 is associated with a better OS and a very significant benefit in terms of DFS. Further analyses are ongoing including disease monitoring from diagnosis to the last follow-up to identify the potential of transplantation timing on the graft versus leukemia effect. Table 1. Table 1. Disclosures Nicolini: Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Ariad Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Obesity is associated with an increased risk of mortality from cardiovascular causes and from malignancies while meta-analyses have evidenced a significant association between an elevated body mass index (BMI) and the risk to develop certain hematological malignancies including acute myeloid (AML) and acute lymphoid leukemia (ALL). Adipocytes are present in the bone marrow were it promote leukemic cells survival and resistance to treatment through the production of amino acids, free fatty acids, pro-inflammatory adipokines and cytokines. Obesity modifies the pharmacokinetic of numerous drugs while obese patients may be undertreated due to dosage capping based on ideal body weight. In addition, obesity increases the risk of treatment-related complication. Obesity adversely affects outcome in pediatric ALL (Butturini et al, J Clin Oncol 2007) and AML (Inaba et al, Cancer 2012). In contrast two retrospective studies based on the analysis of 63 (Lin et al, Leuk Lymphoma 2012) and 329 cases (Lee et al, Ann Hematol 2012) did not found any significant association between obesity and disease outcome in adult patients treated for AML. Here we have investigated whether the body mass index, determined at the time of diagnosis could impact disease outcome in adult patients treated for acute leukemia (AL). A total of 531 consecutive AL patients entered into clinical trials in our Institution between 1994 and 2012 were analyzed retrospectively. They included 343 AML, 146 ALL (102 B-lineage ALL, 41 T-lineage ALL and 3 undifferentiated cases) and 42 acute promyelocytic (APL) leukemias. Based on data collected at the time of diagnosis, BMI was calculated as weight (kg) divided by the square of height (m). Patients were stratified according to the World Health Organization (WHO) BMI classification: underweight (BMI < 18.5), normal weight (BMI 18.5 to Overall, median BMI was 25.7 (16.5 - 46). Two hundred and thirty-three (54.1%) patients were under/normal weight, whereas 197 (45.9%) patients were overweight/obese. An increased BMI (>25) was associated with age > 60 (p 33% (p=0.049). The CR rate after 1stinduction course in underweight, normal, overweight and obese were 78.9%, 79.5%, 80.3%, and 90.1%, respectively. These differences were not statistically significant. The same results were observed when the comparisons were restricted to ALL, AML, in younger or older patients. With a 4.7 years median follow-up (95%CI: 4.0-5.1), median disease-free survival (DFS) and median overall survival (OS) were 13.3 and 22.1 months in AML and 20.8 and 36.5 months in ALL respectively. Medians were not reached in APL. Median OS and DFS (with 95% CI) were 23.1 (13.8-31.6 ) and 29.5 (18-34.1), 17.6 (13.7-22.8) and 32.1 (25.1-36.9), 17.9 (12.1-24.1) and 26.5 (18.6-41.9), and 20.3 (13.4-27.5) and 23.5 (20.3-32.4) months in underweight, normal, overweight and obese, respectively. These differences were not significant. There was no significant impact of BMI on complete response rate, DFS and OS in patients from the whole cohort when considering a cut-off for BMI at 25, and when analyzing according to age, AL subtypes, or to cytogenetics. Only BMI in patients with T- cell lineage ALL showed a significant impact on survival. In patients with BMI >25, median DFS was not reached with a 3-year DFS at 76%, while median DFS was 16.1 months with 3-year DFS at 13% for those with BMI 25 versus 28.3 months in those with BMI These findings provide further evidence that initial body size may have a potential prognostic impact in some subset of leukemia, and more specifically in T cell lineage-ALL. In this AL subtype, validation in larger prospective studies is however warranted. Disclosures Wattel: Novartis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Jannsen: Consultancy, Honoraria, Research Funding; Pierre Fabre: Research Funding. Michallet:Genzyme: Consultancy; Oseus: Consultancy; Novartis: Research Funding; Celgene: Research Funding; BMS: lectures Other; Astellas: lectures Other; MSD: lectures Other. Nicolini:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy; Ariad: Honoraria; BMS: Honoraria.

Auteur(s) : Clelia Moulin1, Sebastien Debarbieux1, Sophie Ducastelle-Lepretre2, Nicole Fabien3, Lauriane Depaepe4, Cecile Veysseyre-Balter3, Veronique Fremeaux-Bacchi5, Sylvie Isaac4, Brigitte Balme6, Luc Thomas1 1Dermatology Department, HCL Lyon Sud 69495 Pierre Benite, France 2Haematology Department, HCL Lyon Sud 69495 Pierre Benite, France 3University of Lyon, Department of Immunology; INSERM U851; HCL Lyon-Sud, F-69495 Pierre-Benite, France 4Pathology department, HCL Lyon Sud, [...]

Abstract 2954 Background: The serum free light chain (sFLC) analysis has been used for the diagnosis and monitoring of plasma cell dyscrasias and has proved its usefulness in disease treatment response in multiple myeloma (MM). Some studies have evaluated the prognostic value of the sFLC levels expressed as K/L ratio (sFLCR) at diagnosis. In contrast, performing this analysis during patient's follow up and on therapy is still not very well defined yet. Aim: Our first objective was to evaluate the impact of sFLCR, measured at diagnosis in MM patients, on the progression free survival (PFS) and overall survival (OS); the second objective was to assess the importance of sFLC analysis during the follow-up especially for relapse/progression detection comparing to concomitant monoclonal-protein (M-p) traditional serum protein electrophoresis (sPE). Methods: Between years 2002 and 2008, we have analysed 174 MM patients for which a concomitant measurement of sFLC and sPE was done during follow-up. Only 118 patients had the sFLCR analysis performed at diagnosis. The sFLC analysis was performed using the Freelite™ test from the Binding site on a BNIIÒ, Dade BehringÓ, and for sPE, analysis was done using a Paragon CZE 2000Ò, Beckman CoulterÓ. There were 92 (53%) males and 82 (47%) females, median age at diagnosis 57 years (34-72), 120 (69%) were IgG (87K&33L), 52 (30%) IgA (41K&11L) and 2 (1%) IgD (1K&1L). According to the ISS, there were 16 (9%) in stage I, 17 (10%) in stage II and 141 (81%) in stage III. Among 61 (35%) FISH analysis done, 31 (51%) detected a chromosome 13 deletion. Twenty six (15%) patients had renal insufficiency. According to the distribution of the different ratios at diagnosis, we have defined three groups: group1 (n=25): patients with 0.133.3 and group3 (n=30): patients with sFLCR Results: After a median follow-up of 38 months [3.3-93.7], the 5-years OS for groups 1, 2 and 3 was 75% [56-100], 60% [47-76] and 40% [23-69] respectively; and the 5-years PFS was 69% [49-96], 43% [31-60] and 29% [15-54] respectively. The multivariate analysis studying age, ISS, sex, cytogenetics and sFLCR, showed that both OS and PFS are worslty affected with a more abnormal sFLCR, hazard ratios (HR) in Figure1. After monitoring all patients, we observed 117 (67%) patients with relapse/progression and 57 (33%) patients were still in response to treatment. In 77 (66%) cases, relapse or progression was detected by concomitant increase of both sFLC and the M-p with a significant earlier increase for sFLC (Figure2A). In 17 (15%) patients, the relapse or progression was characterised by the only increase of sFLC without any increase of the M-p (Figure2B). Contrarily, in 5 (4%) patients there was only an increase of the M-p without increasing the sFLC (Figure2D). Finally, in 18 (15%) patients, the relapse or progression was revealed by the increase of M-p faster than the concerned sFLC (Figure2C). When comparing slopes of increasing sFLC to increasing M-p, we found a very high significant difference (p Conclusion: Our study has showed that abnormal sFLCR at diagnosis affects OS and more strongly the PFS independently of any other concomitant variable. In 81% of patients, sFLC analysis enabled an earlier detection of relapse/progression compared to sPE, this could be very important for early treatment intervention especially for high risk patients. Since there are no uniform recommendations for the use of this analysis during follow-up, we recommend its concomitant use with sPE, waiting for guidelines and we suggest that the sFLCR at diagnosis deserves more focus for its validation as a prognostic factor in MM. Disclosures: No relevant conflicts of interest to declare.